Tag: Liver Directed Therapy

“Cured” – In cancer, this word can evoke a number of emotions. Interestingly, not all these emotions will be as positive as you might think. If you want to spark a heated debate on a Neuroendocrine Cancer patient forum, just mention that you’ve been cured.

I’ve been living with Neuroendocrine Cancer for 8 years so I must be cured, right? Unfortunately not as straightforward as this, and I’m guessing this is the case for many cancers. Doctors clearly need to be careful when saying the word “cured‘ even if there is a small likelihood that a cancer will recur. There’s plenty of ‘conservative’ and alternative terms that can be used, such as ‘stable’, ‘no evidence of disease (NED)’, ‘in remission’ or ‘complete response’. However, I don’t see the latter two much in Neuroendocrine disease circles.

So with all these ‘ifs’ and ‘buts’, what exactly is a cure?

Answering this question isn’t a simple case of ‘yes’ or ‘no’, because it depends on the way that the term ‘cancer’ is defined. It should actually be viewed as an umbrella term for a collection of hundreds of different diseases. They all share the fundamental characteristic of rogue cells growing out of control, but each type of cancer, and each person’s individual cancer, is unique and comes with its own set of challenges.

That’s why it’s very unlikely that there will be one single cure that can wipe out all cancers. That doesn’t mean individual cases of cancer can’t be cured. Many cancers in fact already can be. Scientists aren’t actually on the hunt for a ‘silver bullet’ against all cancers, Quite the opposite. The more scientists get to know each type of cancer inside and out, the greater the chance of finding new ways to tackle these diseases so that more people can survive. Thanks to a much deeper understanding of cell biology and genetics, there exist today a growing number of targeted therapies that have been designed at a molecular level to recognise particular features specific of cancer cells. Along with chemotherapy, surgery and radiotherapy, these treatments—used singly and in combination—have led to a slow, but steady, increase in survival rates. You can definitely count Neuroendocrine Cancer in that category.

Cancer is seen today less as a disease of specific organs, and more as one of molecular mechanisms caused by the mutation of specific genes. The implication of this shift in thinking is that the best treatment for, say, colorectal cancer may turn out to be designed and approved for use against tumors in an entirely different part of the body, such as the breast. We’re certainly seeing that with certain targeted therapies and more recently with Immunotherapy.

Surely a cure is more possible if cancer is diagnosed earlier?

To a certain extent this is true for many types of cancer, not just for NETs. In fact the same scientists did say ….”We detect those attacks when they’re still early, before the cancers have widely spread, at a time when they can still be cured simply by surgery or perhaps surgery and adjuvant therapy, which always works better on smaller tumors.”.

What about Neuroendocrine Tumors (NETs)? Clearly I’m not qualified to make such statements except to say that I am of the opinion that earlier diagnosis is better for any curative scenario. When you read NET guidelines (ENETS/NANETS etc), the word ‘cure’ and ‘curative’ is mentioned in relation to surgery. Bearing in mind that our most expert NET specialists are involved in the drafting of these guidelines, perhaps we should pause and think before dismissing these claims. Having checked ENETS publications, I can see it’s related to certain conditions and factors such as localisation within the organ, tumour size, good resection margins, and a suitable follow-up surveillance.

Clearly with advanced disease, the cancer becomes incurable but treatment for many being palliative to reduce tumor bulk and reduce any symptoms and/or syndrome effects. Despite this, the outlook for metastatic NETs at the lower grades is good. While we’re talking about palliative care, do not confuse this with end of life, that is only one end of the palliative spectrum. It can and is used at the earliest stage of cancer.

Immunotherapy will eventually cure cancer, right?

Immunotherapy will play a huge part in cancer treatment in the future, that we know. But to suggest that it’s a cure is probably overstating its current success. Neuroendocrine Cancer has not been forgotten – you can read more about Neuroendocrine Cancer and Immunotherapy here.

I heard the Oncolytic Virus at Uppsala is a cure for NETs?

There is currently no scientific evidence that the Oncolytic Virus (AdVince) can cure humans with Neuroendocrine Cancer. So far it has only been proven in destroying neuroendocrine tumours in mice. The Oncolytic Viruses developed in Uppsala are now being evaluated in phase I clinical trials for neuroendocrine cancer. If you’re not up to speed with this trial, read more here – Oncolytic Virus Uppsala

Isn’t prevention better than a cure?

This old adage is still relevant BUT latest thinking would indicate it is not applicable to all cancers. Scientists claim that 66% of cancer is simply a form of ‘bad luck’ and if the claim is accurate, it follows that many cancers are simply inevitable. The thinking suggests that random errors occurring during DNA replication in normal stem cells are a major contributing factor in cancer development confirming that “bad luck” explains a far greater number of cancers than do hereditary and environmental factors. This scientific thinking is a tad controversial so it’s worth remembering that even if, as this study suggests, most individual cancer mutations are due to random chance, the researchers also admit that the cancers they cause may still be preventable. It’s complex!

The newspapers are always talking about breakthroughs and cures for cancer?

Newspapers looking for a good headline will use words such as ‘cure’. Sadly, headlines are generally written by sub-editors who scan the article and look to find a ‘reader-oriented angle’ for the heading. They either can’t or don’t have time to understand what’s actually being said. Unfortunately this then leads to people sharing what is now a misleading article without a thought for the impact on those who are worried about the fact they have cancer and whether it can be cured or not. There’s also a lot of fake health news out there – check out my article series about the problems with the internet and ‘Miracle Cures’.

To cure, they must know the cause?

To a certain extent, that’s very accurate. Have you ever wondered what caused your NETs? I did ponder this question in an article here. The only known cause of NETs is currently the proportion of patients with heredity syndromes – see my article of Genetics and Neuroendocrine Cancer. Interestingly, the NET Research Foundation recently awarded funding to look at the causes of Small Intestine (SI) NETs (one of the most common types). A scientific collaboration between UCL, Dana-Farber Cancer Institute, UCSF Medical Centre and the UCL Cancer Institute / Royal Free Hospital London. The team’s approach has the potential to identify inherited, somatic (non-inherited) genetic, epigenetic and infectious causes of SI-NETs. The research is questioning whether SI-NETs are caused by DNA changes in later life or by aberrant genes inherited at birth; environmental influences or infectious agents – or is it a combination of all these factors? Very exciting. Read more here.

What would a cure mean to those living with NETs?

This is something that has crossed my mind, even though I don’t believe it will happen in my lifetime. I guess it would be good to get rid of the known remnant tumors left behind from my treatment (and any micrometastases currently not detectable). However, many NET patients are living with the consequences of cancer and its treatment, including surgery, chemotherapy, biological therapy, somatostatin analogues, radionuclide therapy, liver directed therapy, and others. Many of these effects would remain – let’s face it, a cure is not going to give me back bits of my small and large intestine, liver and an army of lymph nodes. So support for those living with NETs would need to remain despite a cure.

Summary

The emotional aspect of the word ‘cured’ seems to be an issue across many cancers and it’s certainly very controversial in NET circles. The world has still not cured the many cancers that exist. But over the next five to ten years the era of personalised medicine could see enormous progress in making cancer survivable. I think both doctors and patients need to take a pragmatic view on the ‘cured’ word and to end this article I wanted to share an interesting quote I found whilst researching.

I recently wrote a blog called Neuroendocrine Cancer – Exciting Times Ahead! I wrote that on a day I was feeling particularly positive and at the time, I wanted to share that positivity with you. I genuinely believe there’s a lot of great things happening. Don’t get me wrong, there’s a lot still to be done, particularly in the area of diagnosis and quality of life after being diagnosed. However, this is a really great message from a well-known NET expert.

In an interview with OncLive, Jonathan R. Strosberg, MD, associate professor at the H. Lee Moffitt Cancer Center in Florida, discussed his presentation on NETs at a recent 2016 Symposium, and shed light on the progress that has been made in this treatment landscape.

OncLive: Please highlight some of the main points from your presentation.

Strosberg: The question I was asked to address is whether we’re making progress in the management of NETs, and I think the answer is unequivocally yes. Prior to 2009, there were no positive published phase III trials.

Since then, there have been 8 trials, 7 of which have reached their primary endpoints. So it’s been a decade of significant improvement. And even though none of these studies were powered to look at overall survival as an endpoint, we’re certainly seeing evidence of improvement in outcomes.

OncLive: What are some of the pivotal agents that you feel have impacted the paradigm in the past several years?

Strosberg: The first group is the somatostatin analogs. We use them to control hormonal symptoms like carcinoid syndrome, but with the CLARINET study, we now know that they substantially inhibit tumor growth.

The next significant drug we use in this disease is everolimus (Afinitor), an oral mTOR inhibitor, which is now approved in several indications based on positive phase III studies. The first was in pancreatic NETs and subsequently, based on the RADIANT-4 trial, it was also approved in lung and gastrointestinal NETs. So that was an important advance.

The next important category of treatment is radiolabeled somatostatin analogs, otherwise known as peptide receptor radiotherapy. The one that’s been tested in a phase III trial is lutetium dotatate, also known as Lutathera. It was tested in patients with progressive midgut NETs and showed a very substantial 79% improvement in progression-free survival, and a very strong trend toward improvement in overall survival, which we hope will be confirmed upon final analysis.

OncLive: Are we getting better at diagnosing and managing the treatment of NETs?

Strosberg: Certainly. I think pathologists are better at making the diagnosis of a NET, rather than just calling a cancer pancreatic cancer or colorectal cancer. They’re recognizing the neuroendocrine aspects of the disease, and doing the appropriate immunohistochemical staining.

We also have better diagnostic tools. We used to rely primarily on octreoscan, and in many cases we still do, but there is a new diagnostic scan called Gallium-68 dotatate scan, also known as Netspot, which has substantially improved sensitivity and specificity. It’s not yet widely available, but it is FDA approved and hopefully will enable better diagnosis as well as staging in the coming years.

And, with the increase in number of phase III studies, we’re developing evidence-based guidelines, which will hopefully lead to more standardization, although knowing how to sequence these new drugs is still quite challenging.

OncLive: With sequencing, what are the main questions that we’re still trying to answer?

Strosberg: If we take, for example, NETs of the midgut, beyond first-line somatostatin analogs, physicians and patients often face decisions regarding where to proceed next, and for some patients with liver-dominant disease, liver-directed therapies are still an option.

For others, everolimus is a systemic option, and then hopefully lutetium dotatate will be an option based on approval of the drug, which is currently pending. Knowing how to choose among those 3 options is going to be a challenge, and I think there will be debates. Hopefully, clinical trials that compare one agent to another can help doctors make that choice. It’s even more complicated for pancreatic NETs. Beyond somatostatin analogs, we have about 5 choices—we have everolimus, sunitinib (Sutent), cytotoxic chemotherapy, liver-directed therapy, and peptide receptor radiotherapy. It’s even more challenging in that area.

OncLive: Are there any other ongoing clinical trials with some of these agents that you’re particularly excited about?

Strosberg: There’s a trial that is slated to take place in Europe which will compare lutetium dotatate with everolimus in advanced pancreatic NETs, and I think that’s going to be a very important trial that will help us get some information on both sequencing of these drugs, as well as the efficacy of Lutathera in the pancreatic NET population, based on well-run prospective clinical trials. I’m particularly looking forward to that trial.

OncLive: Looking to the future, what are some of the immediate challenges you hope to tackle with NETs?

Strosberg: One area of particular need is poorly differentiated neuroendocrine carcinomas. That’s a field that’s traditionally been understudied. There have been very few prospective clinical trials looking at this particular population, and we’re hoping that will change in the near future. There are a number of trials taking place looking at immunotherapy drugs. If these agents work anywhere in the neuroendocrine sphere, they are more likely to work in poorly differentiated or high-grade tumors, in my opinion, given the mutational profile of these cancers. So that’s something I’m particularly looking forward to being able to offer these patients something other than the cisplatin/etoposide combination that goes back decades, and is of short-lasting duration.

See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-24/expert-discusses-recent-progress-in-net-management#sthash.ypkilX2A.dpuf

Thanks for reading

Ronny

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